Methods and materials for reducing suppression of immune function

ABSTRACT

This document provides methods and materials involved in reducing suppression of immune function in mammals. For example, methods and materials for (a) identifying a mammal as having an elevated level of CD14 + /DR −  cells (e.g., CD14 + /DR −  monocytes) and (b) administering RU486 (mifepristone; or drugs with a similar functional profile) to the identified mammal under conditions that change the ratio of CD14 + /HLA-DR −  cells to CD14 + /HLA-DR +  cells as well as methods and materials for (a) identifying a mammal as being likely to experience an elevated level of CD14 + /DR −  cells (e.g., CD14 + /DR −  monocytes) and (b) administering RU486 (mifepristone; or drugs with a similar functional profile) to the identified mammal under conditions that reduce the degree to which the mammal develops CD14 + /DR −  cells are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/006,536, filed Sep. 20, 2013, which is a National Stage applicationunder 35 U.S.C. §371 and claims benefit of International Application No.PCT/US2012/032321, having an International Filing Date of Apr. 5, 2012,which claims the benefit of U.S. Provisional Application Ser. No.61/473,414, filed Apr. 8, 2011. The disclosure of the prior applicationsare considered part of (and are incorporated by reference in) thedisclosure of this application.

BACKGROUND

1. Technical Field

This document relates to methods and materials involved in reducingsuppression of immune function in mammals. For example, this documentprovides methods and materials for (a) identifying a mammal as having anelevated level of CD14⁺/HLA-DR⁻ cells (e.g., CD14⁺/HLA-DR⁻ monocytes)and (b) administering RU486 (mifepristone) to the identified mammalunder conditions that change the ratio of CD14⁺/HLA-DR⁻ cells toCD14⁺/HLA-DR⁺ cells. This document also provides methods and materialsfor (a) identifying a mammal as being likely to experience an elevatedlevel of CD14⁺/HLA-DR⁻ cells (e.g., CD14⁺/HLA-DR⁻ monocytes) and (b)administering RU486 (mifepristone) to the identified mammal underconditions that reduce the degree to which the mammal developsCD14⁺/HLA-DR⁻ cells.

2. Background Information

The immune system of a mammal is a system of biological structures andprocesses that helps protect the mammal from diseases by identifying andkilling pathogens and tumor cells. A monocyte is one type of white bloodcell that is part of the immune system. Monocytes can have several rolesin the immune system. For example, monocytes can migrate to sites ofinfection and differentiate into macrophages and dendritic cells.Alternatively, monocytes can differentiate into agents acting tosuppress immunity characterized by the loss of HLA-DR (or DR for short),an HLA class II marker.

SUMMARY

This document provides methods and materials involved in reducingsuppression of immune function in mammals. For example, this documentprovides methods and materials for (a) identifying a mammal as having anelevated level of CD14⁺/DR⁻ cells (e.g., CD14⁺/DR⁻ monocytes) and (b)administering RU486 (mifepristone) to the identified mammal underconditions that change the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cellssuch that as a ratio there are less CD14⁺/DR⁻ cells relative toCD14⁺/DR⁺ cells. While not being limited to any particular mode ofaction, the administration of RU486 can alter the ratio of CD14⁺/DR⁻cells to CD14⁺/DR⁺ cells through changes in polypeptide expression(e.g., an increase in HLA-DR polypeptide expression by at least aportion of the mammal's CD14⁺/DR⁻ cells), altered differentiation, orselective killing (e.g., killing of more CD14⁺/DR⁻ cells than killing ofCD14⁺/DR⁺ cells). Having the ability to reduce the number of CD14⁺/DR⁻cells or the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cells within a mammalcan allow clinicians and patients to reduce the immunosuppressiveeffects caused by CD14⁺/DR⁻ cells. In some cases, reducing the number ofCD14⁺/DR⁻ cells or the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cellswithin a mammal can result in enhanced immune function within a mammal.

This document also provides methods and materials for (a) identifying amammal as being likely to experience an elevated level of CD14⁺/DR⁻cells (e.g., CD14⁺/DR⁻ monocytes) and (b) administering RU486(mifepristone) to the identified mammal under conditions that reduce thedegree to which the mammal develops CD14⁺/DR⁻ cells. Having the abilityto reduce the number of CD14⁺/DR⁻ cells that may develop within a mammalcan allow clinicians and patients to reduce the immunosuppressiveeffects that can occur when a mammal develops an increased number ofCD14⁺/DR⁻ cells. In some cases, reducing the number of CD14⁺/DR⁻ cellsthat may develop within a mammal can result in the mammal experiencingan enhanced immune function as compared to the level of immune functionthe mammal would experience had more CD14⁺/DR⁻ cells been allowed todevelop.

As described herein, treating cells with RU486 while the cells areexposed to conditions that result in formation of CD14⁺/DR⁻ cells canresult in the development of less CD14⁺/DR⁻ cells. Having the ability toreduce the number of CD14⁺/DR⁻ cells that develop can enhance immunefunction for patients such as major surgery patients, burn victimpatients, patients undergoing chemotherapy and/or radiation treatment,sepsis patients, patients suffering from an infectious disease, andcancer patients. In some cases, having the ability to reduce the numberof CD14⁺/DR⁻ cells that develop can enhance immune function and allowclinicians to treat various medical conditions such as cancer, sepsis,and infectious diseases more effectively.

In general, one aspect of this document features a method for reducingthe number of CD14⁺/DR⁻ cells or the ratio of CD14⁺/DR⁻ cells toCD14⁺/DR⁺ cells of within a mammal. The method comprises, or consistsessentially of, (a) identifying a mammal as having an elevated level ofCD14⁺/DR⁻ cells, and (b) administering mifepristone to the mammal underconditions wherein the number of CD14⁺/DR⁻ cells or the ratio ofCD14⁺/DR⁻ cells to CD14⁺/DR⁺ cells within the mammal is reduced. Themammal can be a human. The mammal can have sepsis or cancer. Theelevated level of CD14⁺/DR⁻ cells can be a level wherein greater than 10percent (e.g., greater than 13.5 percent or greater than 15 percent) ofCD14⁺ cells are CD14⁺/DR⁻ cells. The mifepristone can be administered inan amount, at a frequency, and for a duration effective to reduce thenumber of CD14⁺/DR⁻ cells within the mammal by at least 10 percent. Theamount can be between about 4 mg and about 200 mg per day. The frequencycan be between about once a day to about once a week. The duration canbe between about one day and about three months. The number of CD14⁺/DR⁻cells within the mammal can be reduced by at least 10 percent. Thenumber of CD14⁺/DR⁻ cells within the mammal can be reduced by at least20 percent. The CD14⁺/DR⁻ cells can be CD14⁺/DR⁻ monocytes.

In another aspect, this document features a method for reducing thenumber of CD14⁺/DR⁻ cells that may be develop in a mammal. The methodcomprises, or consists essentially of, (a) identifying a mammal as beinglikely to experience an elevated level of CD14⁺/DR⁻ cells, and (b)administering mifepristone to the mammal under conditions wherein thenumber of CD14⁺/DR⁻ cells developed within the mammal is reduced ascompared to the number of CD14⁺/DR⁻ cells developed within a comparablemammal not treated with the mifepristone. The mammal can be a human. Themammal can have sepsis or cancer. The elevated level of CD14⁺/DR⁻ cellscan be a level wherein greater than 10 percent (e.g., greater than 13.5percent or greater than 15 percent) of CD14⁺ cells are CD14⁺/DR⁻ cells.The mifepristone can be administered in an amount, at a frequency, andfor a duration effective to reduce the number of CD14⁺/DR⁻ cellsdeveloped in the mammal by at least 10 percent as compared to the numberof CD14⁺/DR⁻ cells developed within the comparable mammal. The amountcan be between about 4 mg and about 200 mg per day. The frequency can bebetween about once a day to about once a week. The duration can bebetween about one day and about three months. The number of CD14⁺/DR⁻cells developed within the mammal can be reduced by at least 10 percentas compared to the number of CD14⁺/DR⁻ cells developed within thecomparable mammal. The number of CD14⁺/DR⁻ cells developed within themammal can be reduced by at least 20 percent as compared to the numberof CD14⁺/DR⁻ cells developed within the comparable mammal. The CD14⁺/DR⁻cells can be CD14⁺/DR⁻ monocytes.

In another aspect, this document features a method for reducing thenumber of CD14⁺/DR⁻ cells or the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺cells of within a mammal. The method comprises, or consists essentiallyof, administering, to a mammal identified as having an elevated level ofCD14⁺/DR⁻ cells, mifepristone under conditions wherein the number ofCD14⁺/DR⁻ cells or the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cellswithin the mammal is reduced. The mammal can be a human. The mammal canhave sepsis or cancer. The elevated level of CD14⁺/DR⁻ cells can be alevel wherein greater than 10 percent (e.g., greater than 13.5 percentor greater than 15 percent) of CD14⁺ cells are CD14⁺/DR⁻ cells. Themifepristone can be administered in an amount, at a frequency, and for aduration effective to reduce the number of CD14⁺/DR⁻ cells within themammal by at least 10 percent. The amount can be between about 4 mg andabout 200 mg per day. The frequency can be between about once a day toabout once a week. The duration can be between about one day and aboutthree months. The number of CD14⁺/DR⁻ cells within the mammal can bereduced by at least 10 percent. The number of CD14⁺/DR⁻ cells within themammal can be reduced by at least 20 percent. The CD14⁺/DR⁻ cells can beCD14⁺/DR⁻ monocytes.

In another aspect, this document features a method for reducing thenumber of CD14⁺/DR⁻ cells that may be develop in a mammal. The methodcomprises, or consists essentially of, administering, to a mammalidentified as being likely to experience an elevated level of CD14⁺/DR⁻cells, mifepristone under conditions wherein the number of CD14⁺/DR⁻cells developed within the mammal is reduced as compared to the numberof CD14⁺/DR⁻ cells developed within a comparable mammal not treated withthe mifepristone. The mammal can be a human. The mammal can have sepsisor cancer. The elevated level of CD14⁺/DR⁻ cells can be a level whereingreater than 10 percent (e.g., greater than 13.5 percent or greater than15 percent) of CD14⁺ cells are CD14⁺/DR⁻ cells. The mifepristone can beadministered in an amount, at a frequency, and for a duration effectiveto reduce the number of CD14⁺/DR⁻ cells developed in the mammal by atleast 10 percent as compared to the number of CD14⁺/DR⁻ cells developedwithin the comparable mammal. The amount can be between about 4 mg andabout 200 mg per day. The frequency can be between about once a day toabout once a week. The duration can be between about one day and aboutthree months. The number of CD14⁺/DR⁻ cells developed within the mammalcan be reduced by at least 10 percent as compared to the number ofCD14⁺/DR⁻ cells developed within the comparable mammal. The number ofCD14⁺/DR⁻ cells developed within the mammal can be reduced by at least20 percent as compared to the number of CD14⁺/DR⁻ cells developed withinthe comparable mammal. The CD14⁺/DR⁻ cells can be CD14⁺/DR⁻ monocytes.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used to practicethe invention, suitable methods and materials are described below. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting the percent of CD14⁺ cells that are positivefor CD80, CD83, or CD86. The graph also plots the mean fluorescenceintensity (MFI) for HLA-DR staining for the CD14⁺ cells. Control cellswere isolated CD14⁺ cells that were cultured but not exposed to cancercells or RU486. The 0, 5, and 20 labeled bars are for isolated CD14⁺cells exposed to cancer cells and treated with 0, 5, or 20 μM,respectively, of RU486.

DETAILED DESCRIPTION

This document provides methods and materials involved in reducingsuppression of immune function in mammals. For example, this documentprovides methods and materials for (a) identifying a mammal as having anelevated level of CD14⁺/DR⁻ cells (e.g., CD14⁺/DR⁻ monocytes) and (b)administering RU486 (mifepristone) to the identified mammal underconditions that change the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cellssuch that as a ratio there are less CD14⁺/DR⁻ cells relative toCD14⁺/DR⁺ cells. This document also provides methods and materials for(a) identifying a mammal as being likely to experience an elevated levelof CD14⁺/DR⁻ cells (e.g., CD14⁺/DR⁻ monocytes) and (b) administeringRU486 (mifepristone) to the identified mammal under conditions thatreduce the degree to which the mammal develops CD14⁺/DR⁻ cells.

Any type of mammal identified as having an elevated level of CD14⁺/DR⁻cells (e.g., CD14⁺/DR⁻ monocytes) or as being likely to experience anelevated level of CD14⁺/DR⁻ cells (e.g., CD14⁺/DR⁻ monocytes) can betreated with RU486 as described herein. For example, humans, monkeys,cows, sheep, horses, dogs, cats, rats, and mice can be treated withRU486 to reduce the level of CD14⁺/DR⁻ cells (e.g., an absolute level ofCD14⁺/DR⁻ cells or the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cells) orthe degree of CD14⁺/DR⁻ cell development, thereby reducing suppressionof immune function as the presence of elevated levels of CD14⁺/DR⁻ cellscan result in general immune suppression. For example, CD14⁺/DR⁻suppressive monocytes can contribute to systemic immune suppression, canprevent the differentiation of monocytes into antigen presenting cells,and can directly inhibit T cell function.

RU486 (mifepristone) is a progesterone receptor modulator andanti-glucocorticoid. In some cases, other progesterone receptormodulators such as Ulipristal acetate, Asoprisnil, and CDB-4124 can beused alone or in combination with other anti-glucocorticoids such ascyproterone, progesterone, and/or DHEA as described herein as analternative to RU486 or in addition to RU486.

As described herein, RU486 can prevent or at least partially inhibit theconversion of normal monocytes into suppressive monocytes or canre-program or re-direct differentiation of at least some suppressivemonocytes back into normal monocytes or immune stimulating cells such asdendritic cells. In some cases, RU486 can be used as a prophylactic toprevent or at least partially inhibit the differentiation of suppressivemonocytes for conditions where suppressive monocytes may occur (e.g.,trauma, major surgery, burns, chemotherapy, radiation treatment, cancer,or sepsis). In some cases, RU486 can be used as supportive care toconditions with suppressive monocytes to prevent or at least partiallyinhibit additional generation of suppressive monocytes. In some cases,RU486 can be used to treat conditions with severe levels of suppressivemonocytes to reduce or eliminate the existence of suppressive monocytesor to restore pro-inflammatory/pro-immune function to the monocytes incases where patients are undergoing other treatments. Such conditionscan include, without limitation, conditions where the patient hassepsis, cancer, trauma, burns, or an infectious disease.

Any appropriate method can be used to identify a mammal as having anelevated level of CD14⁺/DR⁻ cells (e.g., CD14⁺/DR⁻ monocytes) or asbeing likely to experience an elevated level of CD14⁺/DR⁻ cells (e.g.,CD14⁺/DR⁻ monocytes). For example, the level of CD14⁺/DR⁻ cells within amammal having or suspected of having or developing a particular medicalcondition (e.g., cancer, sepsis, autoimmunity, trauma, or infection) canbe determined and compared to cut-off values of CD14⁺/DR⁻ cells for thatparticular condition or values obtained from healthy volunteers toassess whether the level is a normal level, an elevated level (e.g., ahigh level of CD14⁺/DR⁻ cells), or a reduced level (e.g., a low level ofCD14⁺/DR⁻ cells). It is noted that healthy volunteers can have anaverage of about 8.5±2.5 percent of all CD14⁺ cells within a bloodsample as DR⁻. In some cases, an elevated level of CD14⁺/DR⁻ cells canbe any level that indicates that greater than about 12 percent (e.g.,greater than about 13 percent, greater than about 13.5 percent, greaterthan about 14 percent of CD14⁺ cells, greater than about 15 percent, orgreater than about 16 percent) within the circulating blood of a mammalare DR⁻.

The level of CD14⁺/DR⁻ cells can be determined using a sample (e.g., ablood sample) obtained from the mammal to be assessed. Once obtained,the sample can be treated such that the level of CD14⁺/DR⁻ cells can bedetermined. Standard cell staining and immunoflourescence techniques(e.g., flow cytometry) can be used to determine the level of CD14⁺/DR⁻cells. For example, anti-CD14 and anti-HLA-DR antibodies can be used toperform flow cytometry in order to determine the level of CD14⁺/DR⁻cells present within a sample. In some cases, nucleic acid-based assayscan be used to assess the level of CD14⁺/DR⁻ cells. For example, theamount of particular transcripts (e.g., CD14 or DR transcripts) can bedetermined in whole blood using techniques such as quantitative PCR.

Once the level of CD14⁺/DR⁻ cells is determined to be an elevated levelfor a mammal (e.g., an elevated level of CD14⁺/DR⁻ cells as determinedby an elevated ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cells), the mammalcan be treated with RU486 as described herein. In some cases, a mammalsuspected to develop an elevated level of CD14⁺/DR⁻ cells can be treatedwith RU486 as described herein. A composition containing RU486 can beadministered to a mammal using any appropriate route of administrationincluding, without limitation, oral, intraveanous, and intraperitonealroutes of administration. In addition, a composition containing RU486can be administered to an identified mammal in an amount, at afrequency, and for a duration effective to change the ratio of CD14⁺/DR⁻cells to CD14⁺/DR⁺ cells such that as a ratio there are less CD14⁺/DR⁻cells relative to CD14⁺/DR⁺ cells. In some cases, a compositioncontaining RU486 can be administered to an identified mammal in anamount, at a frequency, and for a duration effective reduce the degreeto which the mammal develops CD14⁺/DR⁻ cells.

Effective doses can vary, as recognized by those skilled in the art,depending on the severity of the condition (e.g., level of CD14⁺/DR⁻cells), the route of administration, the sex, age and general healthcondition of the subject, excipient usage, the possibility of co-usagewith other therapeutic treatments, and the judgment of the treatingphysician.

An effective amount of a composition containing RU486 can be any amountthat changes the ratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cells such thatas a ratio there are less CD14⁺/DR⁻ cells relative to CD14⁺/DR⁺ cells,without producing significant toxicity to the mammal. In some cases, aneffective amount of a composition containing RU486 can be any amountthat reduces the degree to which the mammal develops CD14⁺/DR⁻ cells.For example, an effective amount of RU486 can be from about 2 mg/kg toabout 10 mg/kg (e.g., from about 4 mg/kg to about 10 mg/kg, from about4.5 mg/kg to about 10 mg/kg, from about 5 mg/kg to about 10 mg/kg, orfrom about 6 mg/kg to about 10 mg/kg). In some cases, between about 150mg and about 250 mg (e.g., between about 175 mg and about 250 mg,between about 200 mg and about 250 mg, between about 150 mg and about225 mg, between about 150 mg and about 200 mg, or about 200 mg) of RU486can be administered to an average sized human (e.g., about 70 kg) dailyfor between one and 30 weeks (e.g., between two and 30 weeks, betweenthree and 30 weeks, between four and 30 weeks, between four and 20weeks, or 28 days). If a particular mammal fails to respond to aparticular amount, then the amount of RU486 can be increased by, forexample, two fold. After receiving this higher amount, the mammal can bemonitored for both responsiveness to the treatment and toxicitysymptoms, and adjustments made accordingly. The effective amount canremain constant or can be adjusted as a sliding scale or variable dosedepending on the mammal's response to treatment. Various factors caninfluence the actual effective amount used for a particular application.For example, the frequency of administration, duration of treatment, useof multiple treatment agents, route of administration, and severity ofthe condition (e.g., level of CD14⁺/DR⁻ cells) may require an increaseor decrease in the actual effective amount administered.

The frequency of administration can be any frequency that changes theratio of CD14⁺/DR⁻ cells to CD14⁺/DR⁺ cells such that as a ratio thereare less CD14⁺/DR⁻ cells relative to CD14⁺/DR⁺ cells, without producingsignificant toxicity to the mammal. In some cases, an effectivefrequency of administration can be a frequency that reduces the degreeto which the mammal develops CD14⁺/DR⁻ cells. For example, the frequencyof administration can be from about once a month to about once a day, orfrom about twice a month to about twice a day, or from about three timesa week to about once a day. The frequency of administration can remainconstant or can be variable during the duration of treatment. A courseof treatment with a composition containing RU486 can include restperiods. For example, a composition containing RU486 can be administereddaily over a four week period followed by a two week rest period, andsuch a regimen can be repeated multiple times. As with the effectiveamount, various factors can influence the actual frequency ofadministration used for a particular application. For example, theeffective amount, duration of treatment, use of multiple treatmentagents, route of administration, and severity of the condition mayrequire an increase or decrease in administration frequency.

An effective duration for administering a composition containing RU486can be any duration that changes the ratio of CD14⁺/DR⁻ cells toCD14⁺/DR⁺ cells such that as a ratio there are less CD14⁺/DR⁻ cellsrelative to CD14⁺/DR⁺ cells, without producing significant toxicity tothe mammal. In some cases, an effective duration can be a duration thatreduces the degree to which the mammal develops CD14⁺/DR⁻ cells. Thus,the effective duration can vary from several days to several weeks,months, or years. In general, the effective duration can range induration from several weeks to several months. In some cases, aneffective duration can be for as long as an individual mammal is alive.Multiple factors can influence the actual effective duration used for aparticular treatment. For example, an effective duration can vary withthe frequency of administration, effective amount, use of multipletreatment agents, route of administration, and severity of the conditionbeing treated.

In some cases, a composition containing RU486 can be administered to amammal having cancer in combination with one or more cancer treatmentagents such as cisplatin, radiation, or IL-2 or in combination withsurgery. For example, a kidney cancer patient having an elevated levelof CD14⁺/DR⁻ cells can be administered RU486 in combination with or in atreatment regimen with a kidney cancer treatment agent such as torisel,nexavar, sutent, or IL-2. For example, a glioblastoma cancer patienthaving an elevated level of CD14⁺/DR⁻ cells can be administered RU486 incombination with or in a treatment regimen with a glioblastoma treatmentagent such temazolomide, radiation, or surgery.

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

EXAMPLES Example 1 RU486 Reduces the Production of CD14⁺/DR⁻ Cells

Isolated CD14⁺ cells were co-cultured for three days with a renal celltumor line (ACHN) at a 1:10 ratio in DMEM supplemented with 5% HABS.Either 0, 5, or 20 μM of RU486 was added to the culture on day 0. Afterthree days in culture, non-adherent cells were collected from each ofthe T-25 flasks, washed, and replated in Cellgenix medium containingGM-CSF for two days. After the two days, the non-adherent cells werecollected, washed, and resuspended in Cellgenix medium containingGM-CSF, TNFα, and PGE2 for an additional two days to mature.Non-adherent matured cells were collected, washed, stained, and analyzedby flow cytometry using cell surface markers for CD14, CD80, CD83, CD86,and HLA-DR. Control cells were monocytes cultured in a similar manner,but not exposed to the cancer cell line cells and not treated withRU487.

Control monocytes not exposed to cancer cells exhibited HLA-DRexpression, while cells exposed to cancer cells (and not treated withRU486) exhibited much less HLA-DR expression (FIG. 1). Cells exposed tocancer cells and treated with RU486 (5 or 20 μM) exhibited more HLA-DRexpression than cells exposed to cancer cells and not treated with RU486(FIG. 1). These results demonstrate that treatment with RU486 caninterfere with the generation of immune suppressive monocytes.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method for reducing the number of CD14⁺/DR⁻monocytes or the ratio of CD14⁺/DR⁻ monocytes to CD14⁺/DR⁺ monocyteswithin a mammal, wherein said method comprises: (a) performing a cellstaining or immunofluorescence technique to identify a mammal as havinga level of CD14⁺/DR⁻ monocytes wherein greater than 10 percent of CD14⁺monocytes are CD14⁺/DR⁻ monocytes, and (b) administering mifepristone tosaid mammal, wherein the number of CD14⁺/DR⁻ monocytes or the ratio ofCD14⁺/DR⁻ monocytes to CD14⁺/DR⁺ monocytes within said mammal is reducedfollowing said administration; wherein the mammal has glioblastoma. 2.The method of claim 1, wherein said mammal is a human.
 3. The method ofclaim 1, wherein said level of CD14⁺/DR⁻ monocytes is a level whereingreater than 12 percent of CD14⁺ monocytes are CD14⁺/DR⁻ monocytes. 4.The method of claim 1, wherein said mifepristone is administered in anamount, at a frequency, and for a duration effective to reduce thenumber of CD14⁺/DR⁻ monocytes within said mammal by at least 10 percent.5. The method of claim 4, wherein said amount is between about 4 mg andabout 200 mg per day.
 6. The method of claim 4, wherein said frequencyis between about once a day to about once a week.
 7. The method of claim4, wherein said duration is between about one day and about threemonths.
 8. The method of claim 1, wherein the number of CD14⁺/DR⁻monocytes within said mammal is reduced by at least 10 percent followingsaid administration.
 9. The method of claim 1, wherein the number ofCD14⁺/DR⁻ monocytes within said mammal is reduced by at least 20 percentfollowing said administration.
 10. A method for reducing the number ofCD14⁺/DR⁻ monocytes or the ratio of CD14⁺/DR⁻ monocytes to CD14⁺/DR⁺monocytes within a mammal, wherein said method comprises administeringmifepristone to a mammal identified as having a level of CD14⁺/DR⁻monocytes wherein greater than 10 percent of CD14⁺ monocytes areCD14⁺/DR⁻ monocytes, wherein the number of CD14⁺/DR⁻ monocytes or theratio of CD14⁺/DR⁻ monocytes to CD14⁺/DR⁺ monocytes within said mammalis reduced following said administration; wherein the mammal hasglioblastoma.
 11. The method of claim 10, wherein said mammal is ahuman.
 12. The method of claim 10, wherein said level of CD14⁺/DR⁻monocytes is a level wherein greater than 12 percent of CD14⁺ monocytesare CD14⁺/DR⁻ monocytes.
 13. The method of claim 10, wherein saidmifepristone is administered in an amount, at a frequency, and for aduration effective to reduce the number of CD14⁺/DR⁻ monocytes withinsaid mammal by at least 10 percent.
 14. The method of claim 13, whereinsaid amount is between about 4 mg and about 200 mg per day.
 15. Themethod of claim 13, wherein said frequency is between about once a dayto about once a week.
 16. The method of claim 13, wherein said durationis between about one day and about three months.
 17. The method of claim10, wherein the number of CD14⁺/DR⁻ monocytes within said mammal isreduced by at least 10 percent following said administration.
 18. Themethod of claim 10, wherein the number of CD14⁺/DR⁻ monocytes withinsaid mammal is reduced by at least 20 percent following saidadministration.